Taylor Walter R J, Olupot-Olupot Peter, Onyamboko Marie A, Chimjinda Natenapa, Taya Chiraporn, Pouplin Julie Nguyen Ngoc, Williams Thomas N, Maitland Kathryn, Fanello Caterina A, Day Nicholas P J, Tarning Joel, White Nicholas J, Mukaka Mavuto
Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok, 10400, Thailand.
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
BMC Med. 2025 Jul 1;23(1):397. doi: 10.1186/s12916-025-04153-4.
Despite the 2012 WHO recommendation to add single low dose primaquine (SLDPQ, 0.25 mg/kg body weight) to artemisinin-based combination treatments (ACTs) for blocking the transmission of artemisinin-resistant Plasmodium falciparum, there are currently no weight-based regimens founded on robust evidence.
Applying published safety, transmission blocking and pharmacokinetic data, and exploring pharmacokinetic-pharmacodynamic relationships of age-based dosing of SLDPQ in African children with acute, uncomplicated Plasmodium falciparum, we derived weight-based, stand-alone, ACT-, triple ACT-, and vivax-matched regimens by following allometric dosing principles and simulating PQ exposure (area under the concentration time curve). The ACTs were dihydroartemisinin piperaquine (DHAPP), artesunate pyronaridine (ASPYR), artesunate amodiaquine (ASAQ), artesunate mefloquine (ASMQ), artemether lumefantrine (AL), and ALAQ. Tablet strengths were predefined: 2.5, 3.75, 5, 7.5, and 15 mg, and no tablet fractions were allowed. The maximum mg/kg dose was set at 0.5, and, primarily for ease of ACT co-blistering, 1 tablet = 1 dose. We assessed different mg/kg doses and selected the dosing associated with a predicted median exposure closest to 1200 ng*h/mL, the exposure predicted for a 60 kg individual given 15 mg of PQ.
The designed 8 regimens had 4-8 dosing bands. The stand-alone, DHAPP, and ASPYR regimens contain the full line of PQ tablets and all other regimens, except AL (2.5, 7.5, 15 mg) and ALAQ (2.5, 5, 7.5, 15 mg), use 3.75 mg. The 2.5 mg tablet resulted in a maximum dose of 0.56 mg/kg for ASAQ, as this regimen starts at 4.5 kg body weight, whilst all other regimens start at 5 kg and resulted in 0.5 mg/kg. Substituting 3.75 mg with 5 mg results in maximum doses of 0.56 mg/kg (ASAQ, ASMQ) and 0.63 mg/kg (other regimens), risking greater toxicity. Across all dosing bands, 0.17 - 0.56 mg/kg doses predict exposures of ~ 500 - 2000 ng*mL/h. Regimens with more dosing bands had less variations in exposure.
These regimens offer flexibility for malaria control programmes and guidance for drug manufacturers wishing to co-blister SLDPQ with ACTs. The WHO should reinstate the 3.75 mg tablet for prequalification and determine which regimens should be incorporated into their treatment guidelines to advance malaria elimination.
The trial is registered at ISRCTN, number 11594437.
尽管世界卫生组织在2012年建议在以青蒿素为基础的联合疗法（ACTs）中添加单剂量低剂量伯氨喹（SLDPQ，0.25毫克/千克体重）以阻断青蒿素耐药性恶性疟原虫的传播，但目前尚无基于有力证据的按体重计算的用药方案。
应用已发表的安全性、传播阻断和药代动力学数据，并探索非洲急性、非复杂性恶性疟原虫患儿中基于年龄给药的SLDPQ的药代动力学-药效学关系，我们遵循异速生长给药原则并模拟PQ暴露（浓度-时间曲线下面积），得出了基于体重的、单独使用的、与ACT联合的、三联ACT以及与间日疟匹配的用药方案。ACTs包括双氢青蒿素哌喹（DHAPP）、青蒿琥酯咯萘啶（ASPYR）、青蒿琥酯阿莫地喹（ASAQ）、青蒿琥酯甲氟喹（ASMQ）、蒿甲醚本芴醇（AL）和ALAQ。片剂规格预先确定为：2.5、3.75、5、7.5和15毫克，不允许有片剂碎块。最大毫克/千克剂量设定为0.5，并且，主要为便于ACT联合泡罩包装，1片 = 1剂。我们评估了不同的毫克/千克剂量，并选择了与预测的中位暴露最接近1200纳克·小时/毫升的给药方案，这是给予60千克个体15毫克PQ时预测的暴露量。
设计的8种用药方案有4 - 8个给药区间。单独使用的、DHAPP和ASPYR方案包含全系列的PQ片剂，所有其他方案，除了AL（2.5、7.5、15毫克）和ALAQ（2.5、5、7.5、15毫克），使用3.75毫克。2.5毫克片剂导致ASAQ的最大剂量为0.56毫克/千克，因为该方案从4.5千克体重开始，而所有其他方案从5千克开始，导致最大剂量为0.5毫克/千克。用5毫克替代3.75毫克会导致最大剂量为0.56毫克/千克（ASAQ、ASMQ）和0.63毫克/千克（其他方案），有更大毒性的风险。在所有给药区间，0.17 - 0.56毫克/千克剂量预测的暴露量约为500 - 2000纳克·毫升/小时。给药区间更多的方案暴露量变化较小。
这些方案为疟疾控制项目提供了灵活性，并为希望将SLDPQ与ACT联合泡罩包装的药品制造商提供了指导。世界卫生组织应恢复对3.75毫克片剂的预认证，并确定应将哪些方案纳入其治疗指南以推动疟疾消除。
该试验在国际标准随机对照试验编号注册库（ISRCTN）注册，编号为11594437。
